Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism by which cigarette smoking promotes atherosclerosis remains unclear but may involve the endothelium and leukocytes. We postulated a direct acute effect of cigarette smoking on the endothelium and granulocytes by measuring granulocyte expression of L-selectin (flow cytometry) and serum L- and E-selectin (ELISA) before and after smoking in 12 smokers with peripheral vascular disease (claudicants) and 12 otherwise healthy controls. Mean (S.D.) granulocyte L-selectin, expressed as mean fluorescence intensity (MFI), increased in a dose-dependent fashion from 3.58+/-0.67 and 3.27+/-0.67 in controls and claudicants, respectively, to 3.77+/-0.75 and 3.49+/-0.79 10 min after smoking two cigarettes (p<0.002), and to 4.11+/-0.95 and 3.67+/-0.88 30 min after four cigarettes (p<0.001). Serum L-selectin was lower in claudicants at all time points throughout the study period compared with controls (p<0.005) but neither serum E- nor L-selectin levels changed following smoking. Smoking led to an increase in granulocyte expression of L-selectin, which may be important in granulocyte/endothelial adhesion and thus related to atherosclerosis. The lower serum L-selectin levels in claudicants, and the absence of a rise in serum adhesion molecules on smoking, suggests consumption by activated endothelial receptors that may be part of a negative feedback mechanism.
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PMID:Smoking causes a dose-dependent increase in granulocyte-bound L-selectin. 1216 81

Chronic inflammation is a common feature of end-stage renal disease, which carries a heightened risk of atherosclerosis and other co-morbid conditions. Dialysis treatment per se can bring additional risk factors for inflammation, such as increased risk of local graft and fistula infections, impure dialysate or bio-incompatible membranes. Our study was designed to determine whether a hemodialysis session leads to an acute substantial alteration in the plasma levels of the proinflammatory cytokines interleukin (IL)-6, IL-1beta and tumor necrosis factor (TNF)-alpha, the T-lymphocyte activation factor soluble IL-2 receptor (sIL-2R), and an inflammation mediator and chemotactic granulocyte factor, IL-8, in end-stage renal disease patients receiving chronic intermittent HD. In this study, 21 (12 male/nine female) patients undergoing chronic hemodialysis were enrolled. The acute effect of a hemodialysis session on serum cytokine concentrations was assessed by comparison of pre-hemodialysis and post-hemodialysis determinations. Serum IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha levels were determined with chemiluminescence enzyme immunometric assays. A significant difference was not observed for IL-1beta, IL-6, TNF-alpha, and sIL-2R concentrations in pre-hemodialysis and post-hemodialysis specimens (p>0.05). Serum median (25th-75th percentiles) IL-8 concentration was 69.4 (34.9-110.3) pg/ml before hemodialysis, and decreased to 31.5 (18.0-78.8) pg/ml following hemodialysis (p: 0.006). Clearance of IL-8 increased by 0.47+/-0.08 pg/ml for each unit increase in pre-dialysis IL-8 (p<0.001) and decreased by 5.63+/-2.59 pg/ml for each unit increase in pre-dialysis urea mmol/l (p<0.05). In conclusion, the results of our study demonstrate that a hemodialysis session markedly decreases IL-8 concentration, which is significantly affected by pre-dialysis concentrations, indicating that removal of IL-8 is a concentration gradient-dependent action, but does not change the serum levels of IL-1beta, sIL-2R, IL-6, and TNF-alpha, underlining importance of the structural characteristics of the molecules.
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PMID:Acute effect of hemodialysis on serum levels of the proinflammatory cytokines. 1274 44

The total white blood cell (WBC) count is reported to be an independent predictor of mortality in several prospective studies. We investigated the association between total and differential WBC counts and cigarette smoking habit in a cross-sectional population-based study of 6902 men and 8405 women 39-79 years of age participating between July 1994 and 1997 in the European Prospective Investigation of Cancer (EPIC-Norfolk) study. Main outcome measures included WBC, granulocyte, lymphocyte and monocyte counts measured at a baseline health check and self-reported cigarette smoking habit. The age- and body mass index-adjusted mean total WBC counts were 7.8, 6.4, and 6.2x10(3) per ul (P<0.0001) among male current, former and never smokers, respectively, and 7.4, 6.3 and 6.2x10(3) per ul (P<0.0001), respectively, in women. The greatest absolute and percentage differences between smoking groups were observed for the granulocyte count. Current smoking habit had a stronger effect on mean total WBC counts than cumulative exposure as measured by pack years. Among former smokers mean age- and body mass index-adjusted WBC, granulocyte and lymphocyte counts were inversely related to duration of smoking cessation (P< or =0.02). Smokers who had given up less than 12 months previously had WBC counts substantially lower (6.7 and 6.9x10(3) per ul, respectively, in men and women) than current smokers. In conclusion, the total WBC count and its components (particularly the granulocyte count) are strongly associated with cigarette smoking habit. Smoking cessation may have an almost immediate impact at least on pathophysiologic processes such as inflammation that may be indicated by the WBC count. The apparent almost immediate reversibility of effects of smoking on inflammation, as indicated by the WBC count, may help motivate efforts to stop smoking.
Atherosclerosis 2003 Aug
PMID:Smoking status and differential white cell count in men and women in the EPIC-Norfolk population. 1292 86

A functional myeloperoxidase (MPO) promoter polymorphism, -463GA, has been associated with incidence or severity of inflammatory diseases, including atherosclerosis and Alzheimer's disease, and some cancers. The polymorphism is within an Alu element encoding four hexamer repeats recognized by nuclear receptors (AluRRE). Here we show that peroxisome proliferator-activated receptor gamma (PPARgamma) agonists strongly regulate MPO gene expression through the AluRRE. Opposite effects were observed in granulocyte/macrophage colony-stimulating factor (GMCSF)- versus macrophage colony-stimulating factor (MCSF)-derived macrophages (Mphi): Expression was markedly up-regulated (mean 26-fold) in MCSF-Mphi and down-regulated (34-fold) in GMCSF-Mphi. This was observed with rosiglitazone and three other PPARgamma ligands of the thiazolidinedione class, as well as the natural prostaglandin metabolite 15-deoxy-Delta(12,14) prostaglandin J(2). The selective PPARgamma antagonist, GW9662, blocked both the positive and negative effects on MPO expression. Gel retardation assays showed PPARgamma bound hexamers 3/4, and estrogen receptor-alpha bound hexamers 1/2, with -463A in hexamer 1 enhancing binding. Estrogen blocked PPARgamma effects on MPO expression, especially for the A allele. Charcoal filtration of fetal calf serum eliminated the block of PPARgamma, whereas replenishing the medium with 17beta-estradiol reinstated the block. These findings suggest a model in which estrogen receptor binds the AluRRE, preventing PPARgamma binding to the adjacent site. The positive and negative regulation by PPARgamma ligands, and the block by estrogen, was also observed in transgenic mice expressing the G and A alleles. The mouse MPO gene, which lacks the primate-specific AluRRE, was unresponsive to PPARgamma ligands, suggesting the human MPO transgenes will enhance the utility of mouse models for diseases involving MPO, such as atherosclerosis and Alzheimer's.
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PMID:Peroxisome proliferator-activated receptor gamma ligands regulate myeloperoxidase expression in macrophages by an estrogen-dependent mechanism involving the -463GA promoter polymorphism. 1466 25

As an Old World nonhuman primate, baboons have been extensively used for research on dyslipidemia and atherogenesis. With increasing knowledge about the endothelium's role in the initiation and progression of atherosclerosis, the value of the baboon model can be increased by developing it for research on the role of dysfunctional endothelium in atherogenesis. Toward that goal, we have established and validated methods of isolating and culturing baboon femoral artery endothelial cells (BFAECs) and compared baboon endothelial cellular characteristics with those of humans. Our results indicated that baboon and human endothelial cells share similar growth and culture behaviors. As was the case for human endothelial cells, BFAECs responded to tumor necrosis factor (TNF)-alpha stimulation with increased expression of adhesion molecules (maximum increase for intracellular adhesion molecule (ICAM): 1.76 +/- 0.26-fold; vascular cell adhesion molecule (VCAM): 1.65 +/- 0.25-fold; E-selectin: 2.86 +/- 0.57-fold). However, BFAECs were hyporesponsive to lipopolysaccharide (LPS) (range, 0.25-20 microg/mL) in adhesion molecule expression, whereas 1 microg/mL LPS induced 2.14- to 3.71-fold increases in human endothelial cells. The differential responses to LPS were not related to TLR-2 and toll-like receptor (TLR)-4 expression on the cell surface. And baboon microvascular endothelial cells had similar features as BFAECs. We observed constitutive expression of interleukin (IL)-6, IL-8, granulocyte macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein (MCP)-1 in both human and baboon endothelial cells, and these cytokines were further induced by TNF-alpha and LPS. We also demonstrated that the responses to TNF-alpha or LPS varied among baboons maintained under the same dietary and environmental conditions, suggesting that response may be controlled by genetic factors.
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PMID:Comparative analysis of vascular endothelial cell activation by TNF-alpha and LPS in humans and baboons. 1521 Oct 29

We previously reported that oxidized low-density lipoprotein (Ox-LDL)-induced expression of granulocyte/macrophage colony-stimulating factor (GM-CSF) via PKC, leading to activation of phosphatidylinositol-3 kinase (PI-3K), was important for macrophage proliferation [J Biol Chem 275 (2000) 5810]. The aim of the present study was to elucidate the role of extracellular-signal regulated kinase 1/2 (ERK1/2) and of p38 MAPK in Ox-LDL-induced macrophage proliferation. Ox-LDL-induced proliferation of mouse peritoneal macrophages assessed by [3H]thymidine incorporation and cell counting assays was significantly inhibited by MEK1/2 inhibitors, PD98059 or U0126, and p38 MAPK inhibitors, SB203580 or SB202190, respectively. Ox-LDL-induced GM-CSF production was inhibited by MEK1/2 inhibitors but not by p38 MAPK inhibitors in mRNA and protein levels, whereas recombinant GM-CSF-induced macrophage proliferation was inhibited by p38 MAPK inhibitors but enhanced by MEK1/2 inhibitors. Recombinant GM-CSF-induced PI-3K activation and Akt phosphorylation were significantly inhibited by SB203580 but enhanced by PD98059. Our results suggest that ERK1/2 is involved in Ox-LDL-induced macrophage proliferation in the signaling pathway before GM-CSF production, whereas p38 MAPK is involved after GM-CSF release. Thus, the importance of MAPKs in Ox-LDL-induced macrophage proliferation was confirmed and the control of MAPK cascade could be targeted as a potential treatment of atherosclerosis.
Atherosclerosis 2004 Oct
PMID:Extracellular signal-regulated kinase and p38 mitogen-activated protein kinase mediate macrophage proliferation induced by oxidized low-density lipoprotein. 1538 Apr 45

Atherosclerosis is an inflammatory disease of the arteries. Interleukin-10 (IL-10) is known to be an anti-inflammatory cytokine which might be useful for counteracting the development of atherosclerosis. As long-term systemic cytokine delivery is prohibitively expensive, gene therapy might be a suitable approach. To test this idea, low-density lipoprotein receptor (LDLR) knockout mice were injected with recombinant adeno-associated virus type 2 (AAV)/interleukin-10 virus or AAV/granulocyte macrophage-colony stimulating factor (GM-CSF) virus and then put on a high-cholesterol diet. Upon harvesting the animals at 18 weeks, elevated blood lipids could be documented and AAV/IL-10 and AAV/GM-CSF DNA and mRNA could be found in various mouse organs. The mice receiving the AAV/IL-10 virus had significantly lower levels of atherogenesis (Sudan IV-staining and histology) than the untreated or the AAV/GM-CSF-treated animals, dropping from 53% to 17% (p < 0.05). The aortas of the AAV/IL-10-treated animals displayed higher IL-10 expression and lower CD68 and nitrotyrosine expression. These data are similar to those of Yoshioka et al. [Yoshioka, T, Okada, T, Maeda, Y, et al. Adeno-associatedvirus vector-mediated interleukin-10 gene transfer inhibits atherosclerosis in apolipoprotein E-deficient mice. Gene Ther 2004;11:1772-9] in which AAV/IL-10 was delivered into the tibial muscle of ApoE-deficient mice, instead of tail vein injection used here. These data indicate that systemic AAV/IL-10 gene delivery, with resulting inhibition of inflammation and oxidative stress, was able to limit atherogenesis, and suggest that this approach is worthy of further study.
Atherosclerosis 2006 Sep
PMID:Inhibition of atherogenesis in LDLR knockout mice by systemic delivery of adeno-associated virus type 2-hIL-10. 1630 Jul 68

Recent experimental studies have shown that granulocyte-colony-stimulating factor (G-CSF) enhanced cardiac function after infarction. The concept of direct cytokine or cell-mediated effects on postischemic myocardial function was tested in the setting of human myocardial infarction subjected to percutaneous coronary intervention. In the FIRSTLINE-AMI study 50 consecutive patients with first ST-elevation myocardial infarction were randomly assigned to receive either 10 microg/kg G-CSF for 6 days after percutaneous coronary intervention in addition to standard medication, or standard care alone. G-CSF administration led to mobilization of CD34(+) mononuclear stem cells (MNC(CD34+)), with a 20-fold increase to 64 +/- 37 MNC(CD34+)/microl at day 6 without significant associated changes in rheology, blood viscosity or inflammatory reaction, or any major adverse effects. At 4 months the G-CSF group showed improved left ventricular ejection fraction of 54 +/- 8% versus 48 +/- 4% at baseline (P <0.001), and no evidence of left ventricular end-diastolic remodeling, with a diameter of 55 +/- 5 mm and improved segmental wall thickening (P <0.001); conversely, in control patients left ventricular ejection fraction was 43 +/- 5% at 4 months (P <0.001), with increased left ventricular end-diastolic dimension of 58 +/- 4 mm (P <0.001), and no segmental wall thickening. In conclusion, the FIRSTLINE-AMI study showed that G-CSF administration and mobilization of MNC(CD34+) after reperfusion of infarcted myocardium may offer a pragmatic strategy for preservation of human myocardium and prevention of remodeling without evidence of aggravated atherosclerosis.
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PMID:Effects of granulocyte-colony-stimulating factor on mobilization of bone-marrow-derived stem cells after myocardial infarction in humans. 1650 36

To describe how peripheral immune-parameters reflect the inflammatory alterations of the atherosclerotic plaques in coronary atherosclerosis. We measured general inflammatory markers C-reactive protein (CRP) and granulocyte activity, lymphocyte subpopulations and their state of activation, evaluated circulating Th1/Th2-type cytokines, and specific intracytoplasmic cytokines. We investigated the association of immune-parameters with disease outcome and mortality. Thirty-three patients with acute coronary syndrome (ACS), 62 with stable coronary artery disease (CAD) and 58 healthy controls were studied. Peripheral blood lymphocyte subgroups were quantified by flow cytometry, soluble cytokines and autoantibodies were assessed using enzyme-linked immunosorbent assay (ELISA), while intracellular cytokine levels were measured by flow cytometry after intracellular staining. We found elevated levels of CRP and granulocyte activity in ACS versus CAD (P < 0.001, P = 0.017, respectively). Natural killer (NK) cell percentages were elevated, while percentage of T cells to the total lymphocyte count was slightly decreased in ACS compared to controls (P < 0.0001, P = 0.012, respectively). Both forms of coronary atherosclerosis showed significantly higher percentages of activated T cells than controls when stained for the activation markers HLA-DR3 and CD69(+) (ACS: P < 0.0001, P = 0.002, CAD: P < 0.0001, P = 0.018, respectively). IL-1, IL-4 and IL-10 proved significantly higher in ACS versus controls (P = 0.036, P = 0.01, P < 0.0001 respectively). Th1 to Th2 ratio shifted towards a Th1 dominance in both diseases. Both general proinflammatory markers and activated T cells signify CAD. The orchestrated proinflammatory cascade eventually leads to the development of the disease.
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PMID:TH1/TH2 imbalance, measured by circulating and intracytoplasmic inflammatory cytokines--immunological alterations in acute coronary syndrome and stable coronary artery disease. 1691 3

Smooth muscle cell (SMC) proliferation and migration are key processes that occur in the reparative response to injury after percutaneous coronary intervention and in failed bypass grafts for the treatment of atherosclerosis. In the present study, we generated novel synthetic small interfering RNA (siRNA) molecules targeting the coding region of human early growth response-1 (EGR-1) mRNA that attenuate the expression of EGR-1 and that of fibroblast growth factor-2 (FGF-2) and granulocyte-colony stimulating factor (G-CSF). These agents suppressed SMC proliferation in a dose-dependent and non-toxic manner and blocked SMC regrowth from the wound edge following mechanical injury in vitro. In contrast, the scrambled counterpart did not inhibit SMC proliferation, EGR-1 protein expression or SMC regrowth after injury. These findings demonstrate that EGR-1 siRNA can serve as inhibitors of SMC proliferation and wound repair suggesting that these agents may potentially be useful in the control of vascular proliferative disorders.
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PMID:Suppression of growth factor expression and human vascular smooth muscle cell growth by small interfering RNA targeting EGR-1. 1717 47


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